Sudden cardiac death (SCD) takes the lives of 300,000 U.S. citizens each year, the majority due to ventricular fibrillation (VF). The overall objective of this Program Project is to achieve a better understanding of the underlying mechanisms to guide the development of novel therapies. Project 3 will involve experiments at the tissue and whole organ levels exploring the roles of intracellular Ca (Ca{I}) cycling dynamics, early (EAD) and delayed (DAD) afterdepolarizations in the generation and maintenance of VF, and the reinitiation of VF after unsuccessful defibrillation in failing hearts. In collaboration with the mathematical modeling studies in Project 1, cellular studies in Project 2, and therapeutic development in Project 4, we will use whole heart optical mapping studies to address two Specific Aims.
Aim 1 will investigate the mechanisms of phase-2 and phase-3 EADs and their relationship to arrhythmias in failing rabbit ventricles. Our preliminary results show that phase-3 EADs arising from boundary areas of prolonged and normal repolarization play a critical role in generating triggered activity (TA) initiating VT and VF. We hypothesize that due to electrophysiological remodeling, this mechanism becomes important in ventricular arrhythmogenesis in failing ventricles. The experimental findings will also be complemented by computer simulations by the Project 1 investigator team.
Aim 2 will test the hypothesis that postshock action potential duration (APD) shortening, spontaneous sarcoplasmic reticulum (SR) Ca release and increased Ca{i}-Vm coupling gain (defined as the sensitivity of membrane voltage Vm to elevations in Ca{i}) synergistically promote VF reinitiation and electrical storm by promoting afterdepolarizations in failing ventricles.
Aim 2 a will test the hypothesis that inhibition of spontaneous SR Ca release is an effective antiarrhythmic strategy to suppress postshock DADs, TA and recurrent VF in failing ventricles.
The Aim 2 b will test the hypothesis that apamin-sensitive small-conductance Ca-activated potassium current (I{KAS}) facilitates spontaneous postshock VF recurrences by shortening APD, and that I{KAS} inhibition can prevent recurrent VF in failing ventricles. Successful completion of these research projects will provide new insights into the mechanisms of phase 3 EADs, and help develop new approaches to preventing recurrent VF during electrical storm in failing ventricles.

Public Health Relevance

The proposed research will study the mechanisms of sudden cardiac death due to ventricular arrhythmias, which prematurely takes the lives of more than 300,000 U.S. citizens each year. The goal is to use this information to develop novel therapies to prevent this deadly manifestation of heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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University of California Los Angeles
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